Compositions of salts of salicylamide

ABSTRACT

Pharmaceutical compositions of alkali metal salts of salicylamide are orally administered with significantly improved analgesic, anti-inflammatory, antipyretic and sedative results, as compared with solid oral dosage forms of both salicylamide and the alkali or alkaline earth metal salts of salicylamide. The compositions are administered as solutions formed by dissolving in an aqueous media a composition comprised of a unit dosage amount of an alkali metal salt of salicylamide, an effervescent couple and a nucleating inhibitor.

[ Oct. 9, 1973 COMPOSITIONS OF SALTS OF SALICYLAMIDE A [75] Inventors:Takeru Higuchi; Anwar I-Iussain,

both of Lawrence, Kans.

[73] Assignee: Interx Corporation, Lawrence,

Kans.

22 Filed: May 1, 1972 21 Appl. No.: 249,007

Related US. Application Data [63] Continuation-impart of Ser, Nos.22,049, March 23, 1970, abandoned, and Ser. No. 77,010, Sept. 30, l970,Pat. No. 3,676,549.

[52] US. Cl. 424/44, 424/230 [51] Int. Cl A61k 9/00 [58] Field of Search424/44, 230

[56] References Cited UNITED STATES PATENTS 3,136,692 6/1964 Bandelin424/44 2,904,469 9/1959 Nashed 424/80 OTHER PUBLICATIONS Bates, T. R. etal., J. Pharm. Sci. 58:1468-1470 Dec.

1969, correlation Between the Rate of Dissolution and Absorption ofSalicylamide from Tablet and Suspension Dosage Forms PrimaryExaminer-Shep K. Rose Attorney-Paul L. Sabatine et al.

[57] ABSTRACT Pharmaceutical compositions of alkali metal salts ofsalicylamide are orally administered with significantly improvedanalgesic, anti-inflammatory, antipyretic and sedative results, ascompared with solid oral dosage forms of both salicylamide and thealkali or alkaline earth metal salts of salicylamide. The compositionsare administered as solutions formed by dissolv ing in an aqueous mediaa composition comprised of a unit dosage amount of an alkali metal saltof salicylamide, an effervescent couple and a nucleating inhibitor.

4 Claims, No Drawings COMPOSITIONS OF SALTS OF SALICYILAMIDE CROSSREFERENCE TO RELATED APPLICATION This application is acontinuation-in-part of our copending patent applications U.S. Ser. No.22,049 filed on Mar. 23, 1970 now abandoned and United States Ser. No.77,010 filed on Sept. 30, 1970 now U.S. Pat. No. 3,676,549, bothassigned to the assignee of'the: present application.

BACKGROUND OF THE INVENTION This invention relates to the administrationofpharmaceutical or veterinary compositions. Especially it pertains tothe administration of aqueous solutionsof a unit dosage amount of analkali metal-salt of salicylamide for use as an analgesic, antipyretic,antiinflammatory, or sedative. More especially, the invention pertainstothe administration of such solutionsformed from an effervescentcomposition'which'can be granular, a capsule, a pill or acompressed'tablet;

Salicylamide is widely used in analgesic, antiinflammatory, andantipyretic preparations. There are many conflicting reports, however,as to the efficacy of this drug. salicylamide is a relatively insolubledrug, having a water solubility of only 0.2 percent at 30C. When orallyadministered fromtablets or capsules, a substantial amount ofsalicylamide fails'to dissolve 'during passage through-thegastrointestinaltract and can be recovered in the feces. Often as muchas onethird of the drug is lost'in this manner.

Additionally, a significant portion'ofthe'salicylamide' which does gointo solution is conjugatedduring absorption through the intestinalwalls to'its glucuronide and sulfate derivatives, neither of which hasthe desired rated by reference and is relied upon, there is describedand claimed a means of orally administering effective amounts ofsalicylamide in a beneficially usable form; The invention of saidcopending application, Ser. No. 22,049, resides in an orallyadministrable dosageunit for use as an analgesic, antipyretic,anti-inflammatory, or sedative comprising a unit dosage amount of analkali or alkaline earth metal salt of salicylamide formulated withorally acceptable solidpharmaceutical carrier. In accordance with suchinvention, it'was found that oral administration of alkali and alkalineearth metal salts of salicylamide from solid dosage forms, for" example,tablets, pills, powders, capsules, and the like, providestherapeutically effective blood levels of salicylamide, substantiallyhigher than when salicylamide itself is administered. Dosage formscontaining these salicylamide salts have greater usefulnessasanalgesics, antipyretics, anti-inflammatories and sedatives than dosimilar dosage forms containing salicylamide. Moreover, the two longrecognized major problems with oral salicylamide administration, namely,insolubility and conjugation during absorption, are both improved uponby the oral administration of these salts. Thus, alkali and alkalineearth metal salts of salicylamide dissolve substantially completely inthe gastrointestinal tract and are readily available for absorption,essentially eliminating the problem of the drug simply passing throughthe gastro-intestinal tract. And, significantly, the greateravailability of the drug to the wall of the small intestine overcomesthe problem of inactivation by conjugation during absorption. This isespecially true when the dosage unit is provided with an enteric coatingthat resists solution in gastric fluids but disintegrates in the smallintestine. Through use of an enteric coating, the highly solublesalicylamide salt is presented to a relatively small area of theintestinal wall in high concentration. By presenting a quantity of drughigher than that which can be conjugated by the means available, thebulk of the salicylamide salt is absorbed in a free state. Thus, thelarge quantity of salicylamide salt presented to a small segment of thesmall intestine wall tends to overwhelm or swamp the inactivationmechanism.

While the orally administrable dosage unit of the aforesaid copendingapplication, Ser. No. 22,049, represents a marked advance andcontribution to the medicaland veterinary arts, it has now unexpectedlybeen found, as first disclosed in our copending application, Ser. No.77,010, that oral administration of an aqueous solution-of an alkalimetal salt'of salicylamide, formed from an effervescent compositioncomprised of a unit dosage amount of the salt, provides significantfurther improvement'in therapy, permitting much more rapid absorptionand action, and hence therapeutically effective-'resultsfollowed by oraluse of salicylamide. In this latter referenced application, Ser. No.77,010, the disclosure of which is incorporated by reference and reliedupon herein, there is describedand claimed novel compositions comprisinga salt of salicylamide, an effervescent couple and certain nucleatorinhibitors which inhibitors act to substantially prevent thesalicylamide salt from precipitating in an aqueous like environment. Inthe present application, it has unexpectedly' found that othercommercially available and relatively inexpensive compounds can be usedas nucleator inhibitors to produce both new and useful effervescentcompositions for salicylamide therapy to give a beneficialanalgesic,anti-inflammatory, antipyretic or sedative effect.

SUMMARY OF THE INVENTION Accordingly, it is an immediate object of theinvention to provide a pharmaceutical or veterinary composition ofmatter comprising a salt of salicylamide, an effervescent couple and anucleator inhibitor which composition is useful for a physiologic andpharmacologic effect in the management of health and disease.

It is a further object of this invention to provide a compositioncomprising a salt of salicylamide that overcomes the difficultiesassociated with the prior art.

Yet a further object of this invention is to provide an effervescentcomposition which, when completely dissolved in water and orallyingested, finds use as an analgesic, anti-inflammatory, antipyretic orsedative.

Another object of this invention is to provide an effervescentcomposition for effectively administering salicylamide.

Still another object of this invention is a significant improvement insalicylarnide therapy by orally administering a sparkling aqueoussolution of an alkali metal salt of salicylamide. I

In attaining the objects of this invention, one feature resides in aneffervescent composition comprised of a unit dosage amount of an alkalimetal salt of salicylamide in an orally acceptable, solid pharmaceuticaleffervescent couple. Another feature resides in formulating theeffervescent composition to contain a novel nucleator inhibitor to yielda composition that when dissolved in water produces an effervescingaqueous solution for use as an analgesic, antipyretic, anti-inflammatoryor sedative.

Other objects, features and advantages of this invention will becomemore apparent to those skilled in the art from the detailed descriptionof the invention which follows.

DESCRIPTION OF THE INVENTION In accordance with this invention, it hasbeen found that by orally administering an effervescing solutioncomprised of a unit dosage amount of an alkali metal salt ofsalicylamide, therapeutically effective results for the salicylamide areattained that are substantially higher than when salicylamide itself isadministered and even significantly higher than when its alkali andalkaline earth metal salts are administered in solid oral dosage forms.Dosage forms containing the alkali metal salicylamide salts andcharacterized by the effervescent feature have far greater usefulness asanalgesics, antipyretics, anti-inflammatories, and sedatives than dosolid oral dosage forms containing salicylamide or the alkali andalkaline earth metal salts thereof and not characterized by aneffervescent feature.

Salts of salicylamide useful for the purpose of the present inventioncan be represented by the generic formula:

CONH:

where Me is an alkali .metal cation.

Suitable salts of the above formula are those which do not forminsoluble salts with agents in the effervescent composition, resultingin sedimentation and eventual precipitation of the salicylamide. Variouspharmaceutically acceptable alkali metal salts of salicyl'amide can beadministered from solution. Of these, the sodium and potassium salts arepreferred. Best results are obtained with the sodium salt.

While the orally administrable dosage unit of copending application,Ser. No. 22,049, improves upon both the problem of insolubility andconjugation during absorption, the invention of 'copending application,Ser. No. 77,010, goes even further by providing a means wherebycompositions made into aqueous solutions of alkali metal salts ofsalicylamide are directly,

available for absorption, that is, an effervescentcomposition.

The effervescent composition of the invention, whether granular, acompressed tablet, a pill or a capsule, is prepared in a conventionalmanner from a mixture of an effervescent couple, an alkali metal salt ofsalicylamide, and a nucleating inhibitor.

The effervescent couple of the effervescent composition consists of atleast one each of a solid'acid and a solid basic material which whendissolved in an aqueous media, for example water, reacts with oneanother to produce carbon dioxide, CO which causes effervescence. Theacids that can be used are the pharmaceutically acceptable acids,including organic acids such as malic, fumaric, tartaric, itaconic,maleic, citric, adipic, succinic, malonic or mesaconic acid, and thelike, and mixtures thereof, or a corresponding anhydride such asitaconic anhydride and citriconic anhydride and the like, and it can beinorganic acids such as acid sodium phosphate, sulfamic acid or aphosphonic acid derivative such as disclosed in U.S. Pat. No. 3,325,357.Acid salts can also be used such as the salts of commonly used organicfood acids such as monosodium citrate, potassium acid tartrate,potassium bitartrate, and the like. The basic materials of theeffervescent couple can be any of the pharmaceutically acceptablematerials that react with the acid material with the release of carbondioxide when contacted with an aqueous medium. These include metalcarbonate salts such as alkali or alkaline earth metal carbonates andbicarbonates and mixtures thereof. Examples of suitable materialsinclude lithium, sodium, potassium, magnesium and calcium carbonates, orbicarbonates thereof, ammonium carbonate, ammonium bicarbonate, ammoniumsesquicarbonate, sodium mixtures thereof, and the like. The combinationof certain of these acids and bases results in much more rapideffervescence when placed in water than do other members of the abovegroups. In particular, either citric acid, or a mixture of citric andtartaric acids, and sodium bicarbonate constitute a presently preferredcouple due to their rapid reaction and consequent effervescence.

It will be understood that the range of solid acid and solid basicmaterials in the effervescent compositions of this invention is ratherwide. Inasmuch as the exact proportions, or any particular acid or base,are not necessary, they may be widely varied to suit the exigencies ofthe occasion. The essentially dry effervescent couple, however, is ofcourse substantially stoichiometrically balanced to produce anessentially neutral combination.

The effervescent compositions can additionally contain conventionalpharmaceutical or veterinary additives such as diluents, binders,lubricants, disintegrators, coloring agents and the like. Typically, theamount of these additives can vary over a Wide range, for example about1 mg to 750 mg or higher for each pharmaceutical, effervescentcomposition, or from between about 0.1 percent to 20 percent by weightof the formulation. Typical diluents include dicalcium phosphate,calcium sulfate, lactose, kaolin, mannitol, sorbitol, dry starch, andpowdered sugar. Typical binders include starch, gelatin, sugars such assucrose, molasses, and lactose, natural and synthetic gums such asacacia, sodium alginate, extract of Irish moss, carboxymethylcellulose,methylcellulose, and polyvinylpyrrolidone, polyethylene glycol,ethylcellulose, and waxes. Typical lubricants for use in these dosageforms include boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, and polyethylene glycol. Disintegrators which can bepresent include such agents as starch, methylcellulose, agar, bentonite,cellulose and wood products, alginic acid, guar gum, citrus pulpcarboxymethylcellulose, and sodium lauryl sulfate. If desired,

conventional pharmaceutically acceptable dyes can be incorporated in thedosage unit. Typical surface active compounds includecetyldimethylbenzylammonium bromide, cetyltrimethylammonium bromide, andcetylpyridinum bromide. Typical buffering agents include glycine,alanine, glycylglycine and alanylalanine, and the like.

One important feature of the effervescent compositions of our copendingapplication Ser. No. 77,010 is that it should contain a nucleatinginhibitor, also referred to herein as a nucleating agent, or nucleationinhibiting agent, for example, polyvinylpyrrolidone, methylcellulose orgelatin, which nucleating inhibitor acts to substantially prevent theprecipitation of free salicylamide resulting from the conversion of thesalicylamide salt to its corresponding acid at a pH of l to 8. While theabove nucleating inhibitors, as disclosed in Ser. No. 77,010, were avaluable contribution and advance in the art, it has now beenunexpectedlyfound that the now described pharmaceutically acceptablecompounds are suitable nucleating inhibitors for the purpose of thepresent invention. Other nucleating inhibitors according to this presentinvention include the water soluble synthetic cellulose compoundsethylhydroxyethylcellulose, hydroxyethylcellulose, and sodiumcarboxymethylcellulose, water soluble naturally occurring exudate fromvegetation such as gum arabic, gum karaya and gum tragacanth, watersoluble sea weed product such as agar-agar and carrageen, glycolcompounds such as glycerine, propylene glycol and polyethylene glycol,and complexing agents such as caffeine and xanthene. Other suitablenucleating inhibitors similar to those above listed can be usedaccording to the mode and manner of the invention and these includepolyvinylmethyl ether, polyethylene oxide, locust bean gum, casein andnucleating inhibitors that would be obvious to those skilled in the art.The amount of nucleating inhibitor incorporated in the effervescentcomposition is not critical and it can vary widely. Typically, however,the nucleating inhibitor comprises from between about 0.1 percent toabout 2.0 percent, by weight, of the formulation, or about 1 mg to 1000mg for each effervescent composition.

As hereinbefore mentioned, the effervescent composition, whethergranular, a compressed tablet, a pill, formed into a fiber, suppositoryor a capsule, is prepared in a conventional manner, as for example inRemington s Pharmaceutical Sciences, 1970, Mack Publishing Co., Easton,Pennsylvania. Those skilled in the art are well aware of the standardtechniques which can be used to prepare these solid dosage forms.

Alkali metal salicylamide salts are administered according to thisinvention in the same unit dose amounts conventionally used withsalicylamide. In general each dosage unit for eliciting thedesired'pharmacological response contains from 50 milligrams to 2 gramsof the salicylamide salt. Typically, the dose for an adult human isabout 300 milligrams administered three to five times a day incorporatedin the dosage unit. Usual daily dosage of the alkali metal salicylamidesalts described in more detail also corresponds to that conventionallyassociated with salicylamide, as set forth in the National Formulary,Thirteenth Edition, pages 627 and 628, 1970, published by The AmericanPharmaceutical Association, Washington, D.C., namely up to a totalof nomore than about grams. Typical veterinary dose for sheep and swine isabout 1 to 5 grams one to two times a day, for dogs about 0.25 to 1.0grams one to two times a day, for cats about to 200 mg. one to two timesa day, and the like.

Alkali metal salicylamide salts can be administered in conjunction withother drugs to obtain enhanced efficacy. When this is done, the amountof the alkali metal salicylamide salt in the dosage unit can vary fromthe ranges previously set forth and the amount to be administered can bereadily determined by those skilled in the art. Typical of other drugsthat can be combined with the alkali metal salts of salicylamide toprovide a combination dosage unit are: phenacetin, aspirin, sodiumsalicylate, cafieine, acetaminophen, scopolamine, phenylephrinehydrochloride, glycerol guaiacolate, chlorpheniramine maleate,belladonna alkaloids, dextromethorphan hydrobromide, ephidrinehydrochloride, and phenylpropanolamine hydrochloride.

Unexpectedly good results are obtained when an alkali metal salicylamidesalt is combined with an alkali or alkaline earth metal salt ofacetominophen having the formula:

l NH-C O CH: 1:

wherein Me is an alkali or alkaline earth metal cation of valence n andn is l or 2. Such dosage forms, containing salts of both drugs, areprepared in a conventional manner, as described above. The mole ratio ofthe salicylamide salt to the acetominophen salt can vary in the range of0.25:] to 4:1 but the total unit dosage amount of drug should be from 50milligrams to 2 grams. Though one can depart from these ranges, thetherapeutic effect, a more beneficial oral use of drug, is not present.

'- The following examples will serve to illustrate the invention withoutin any way being limiting thereon.

EXAMPLES l and 2 Weight, Components Grams (1) Sodium salicylamide (drypowder) 200 (2) Sodium Bicarbonate (dry powder) 477 (3) Tartaric Acid(dry powder) 252 (4) Citric Acid (anhydrous) 147 (5) NucleatingInhibitor l5 The proportions of tartaric acid and citric acid in theseexamples may be varied, if desired, but their combined acidity must beequivalent to the above total acidity for an approximately 1 Kg.formulation.

The components (3) and (4) were thoroughly mixed, and the admixturedampened with a granulating agent such as anhydrous methanol or acetone.The damp material was then panned through a No. 14 mesh sieve and driedfor four hours at 40 50C. Component (5), either hydroxy-ethylcellulose(Example 1) or carboxymethylcellulose (Example 2), was next dissolvedinto a 1:1 granulating mixture of methanol and acetone. The component(1) was then mixed with the component (2) and the nucleating inhibitor(5) solution added thereto. This damp material was also panned through aNo. 14 mesh sieve and dried for four hours at 40 50C. Mixing the twodifferent granules provided an effervescent composition suitable fordissolving in an 7 aqueous medium, for example water, and administeringaccording to the invention.

EXAMPLES 3 and 4 In Examples 3 and 4, the procedure used in Examples 1and 2 is followed to yield the desired effervescent composition. Thenucleating inhibitor component is a mixture of carboxymethyl celluloseand hydroxyethylcellulose-in a l:l ratio, Example 3, and a mixture ofhydroxyethylcellulose and gum arabic in a 3:2 ratio, Example 4.

EXAMPLES 5 and 6 Weight, Components Grams (1) Potassium Salicylamide(dry powder) 200 (2) Potassium Carbonate (anhydrous) 77 (3) PotassiumBicarbonate (dry powder) 400 (4) Tartaric Acid 252 (5) Citric Acid(anhydrous) 147 (6) Nucleating inhibitor The procedure used forformulating the compositions of Examples 5 and 6 is as set forth inExamples 1 and 2, except that component (6) consisted of gum tragacanth,and hydroxyethyl cellulose in a 1:4 ratio, Example 5 and caffeine inExample 6.

EXAMPLE 7 Other alkali metal salts of Salicylamide can be formulatedwith a like or different effervescent couple in a similar manner asdescribed in Examples 1 through 6.

To form tablets from an effervescent mixture such as that describedabove, the mixture should advantageously be in granular form in orderthat it will be suffi ciently free-flowing to be easily fed to the diecavity of the tableting machine employed for shaping the tablets.Powders do not flow freely and these powders should be granulated insome convenient fashion. The usual methods of preparing such freeflowing granulations include the heat fusion method, the use of steam orwater injection, or the use of a double granulation method. As is known,when compressed tablets are made according to conventional procedure,lubricants must be added to the granulation to facilitate removal of thetablets from the die cavities of the tableting machine aftercompression. Exemplary of the conventional tableting machines, there maybe mentioned hand punch, rotary and automatic. Any reasonable size andshape of tablet will yield a satisfactory product.

EXAMPLE 8 The following dry powdered components are thoroughly mixed ina laboratory v-blender in the stated porportions, with the particle sizeof the ingredients in the range of 50 to 200 mesh:

Components Percent (l) Citric Acid Anhydrous 63 (2) Sodium Bicarbonate(dry) 35 (3) Nucleating inhibitor 1.5 (4) Buffer 0.5

cessed by heating for 25 to 30 minutes at 1l0 to 120C, to yield a solid,homogenous mixture at room temperature. The solid is next rotarygranulated and redried for one hour at C. Next, the dried granulation isadded to the following:

Components Percent (5) Granulation 90.0 (6) Sodium Salicylamide (dry)8.5 (7) Flavor (spear-mint) 1.24 (8) Dye (light blue) 0.20 (9) Stannousfluoride 0.06

The mixture is thoroughly blended and compressed into tablets by arotary tableting machine. The tablets produced are three-fourths of aninch in diameter, 5/10 of an inch thick, weigh 2.3 grams and have aStrong Cobb hardness of 3-6.

To demonstrate that sodium salicylamide would have improvedbioavailability when used for the purpose of the invention, thedissolution rates of sodium Salicylamide were compared to salicylamideby using 300 milligram half-inch diameter tablets having a thickness ofl millimeter, and prepared with a Carver Press at 10 pounds per squareinch pressure. When placed in simulated gastric fluid (400 milliliters,0.1 Normal HCl) at 37C in a round bottom flask magnetically stirred at60 RPM, the results set forth in Table 1 were obtained.

TABLE 1 Percent Dissolved Elapsed Sodium Time Salicylamide Salicylamidel min. 16 2 min. 34 1 5 min. 68 l 11 min. 97 l 20 min. 2

1 hr. 5 2 hr. 18 4 hr. 32 8 hr. 54 20 hr. 88 40 hr. 97 44 hr. 100

When the dissolution rate for tablets prepared in an identical mannerwere tested, to indicate the bio-availability of sodium Salicylamide,under the same conditions in simulated intestinal fluid (6.80 partsmonobasic potassium phosphate, 1.52 parts sodium hydroxide, 1000 partsdistilled water) of pH 7.5, the following results were obtained, as setforth in Table 2.

TABLE 2 Percent Dissolved Sodium Elapsed Time Salicylamide Salicylamidel min. 15.0 5 min. 78.5 [0 min. 96.8 15 min. 98.5 20 min. 100.0

25 min. 30 min. 6.2 4 hr. 35 min. 33.4 17 hr. 5 min. 89.5 24 hr. l0 min.93.0 26 hr. 25 min. 96.5 46 hr. 30 min. l00.0

To demonstrate the results obtained for sodium salicylamide compared toSalicylamide a standard test for the Component (3) ishydroxypropylmethylcellulose and component (4) is glycine with theblended mixture proincidence of loss of righting reflex is carried outin test animals. The test is performed with a mixed, 10 member colony ofcommercially available rats weighing about to 200 grams. The sodiumSalicylamide and the salicylamide is mixed with 0.5 percent gumtragacanth and administered by gastric gavage at the rate of 1 ml per100 grams of body weight. The test indicated a prostration dose, PD-SOfor salicylamide is 875 (735 to 1040) mg/kg and for sodium salicylamide570 (503 to 643) mg/kg, with a potency ratio of 1.54 (1.24 to 1.91) forsodium salicylamide.

In summary, effervescent compositions containing alkali metal salts ofsalicylamide are provided that can be dissolved in water and then orallyadministered for use as analgesic, antipyretic, anti-inflammatory andsedative effects. While the invention has been described and pointed outwith reference to certain preferred embodiments thereof, those skilledin the art will appreciate that various changes and modifications andsubstitutions can be made without departing from the spirit of theinvention. It is intended, therefore, that the invention be limited onlyby the scope of the claims which follow.

We claim:

1. A composition of matter which effervesces in an aqueous medium toproduce an aqueous effervescing solution for oral administration as ananalgesic, antipyretic, anti-inflammatory or sedative, comprising a unitdosage amount of an alkali metal salt of salicylamide in an orallyacceptable pharmaceutical effervescent couple with an effective amountof ethylhydroxylethylcellulose, hydroxyethylcellulose, sodiumcarboxymethylcellulose, gum arabic, gum karaya, gum tragacanth,carrageen, caffeine, xanthine, locust bean gum, casein and polyethyleneglycol that acts to substantially prevent the precipitation of freesalicylamide resulting from the conversion of the salicylamide salt toits corresponding acid at a pH of l to 8.

2. The composition of matter as defined by claim 1 further comprising analkali or alkaline earth metal salt of acetominophen.

3. The composition of matter as defined by claim 1 further comprisingglycine, alanine, glycyglyane and alanylalanine.

4. An effervescing, aqueous solution for use as an analgesic,antipyretic, anti-inflammatory 0r sedative, comprised of water and thecomposition of matter as defined by claim 1.

' l'i ta new: 9; 1973 Patent No. 3,764 668 Inventor) Takeru Higuchi andArmar Hussain It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

IN THE ASSIGNEE'S NAB/IE:

Kindly amend the assignee of the above-identified patent to read:

-- mlERx Research Corporation Signed vand sealed this 8th day of October1974.

(SEAL) Attest:

MCCOY M. GIBSON JR. 0. MARSHALL DANN Attesting Officer Commissioner ofPatents USCOMM-DC 60376-P69 FORM PC3-1050 (1069) 1* u.s. GOVERNMENTPRINTING OFFICE 1909 D--S66-334,

2. The composition of matter as defined by claim 1 further comprising analkali or alkaline earth metal salt of acetominophen.
 3. The compositionof matter as defined by claim 1 further comprising glycine, alanine,glycyglyane and alanylalanine.
 4. An effervescing, aqueous solution foruse as an analgesic, antipyretic, anti-inflammatory or sedative,comprised of water and the composition of matter as defined by claim 1.